Osteoporosis is a common disease and frequently-occurring disease in old people, especially in women during or after menopause. With the change of the contemporary disease, WHO lists osteoporosis as one of the three diseases which happens in middle aged and elderly people, ranking NO.7 in the common diseases. About 50% of women over the age of 50 and 20% of men suffer fractures caused by osteoporosis. The current common drug for the treatment of osteoporosis are drugs of anti-bone resorption, drugs of promoting bone formation, drugs having the dual role of the former two drugs, biological drugs, or other drugs, but most of them have side effects, and new drugs for treatment are in urgent need.
Cathepsin is a principal member of the cysteine proteases family, more than 20 species of which have been found in the biosphere, and 11 species mainly exist in human body, which closely associates with many kinds of major diseases such as human tumor, osteoporosis, arthritis, and so on. The subtype of cathepsin consists of cathepsin B, F, H, L, K, S, W and Z. Cathepsin S mainly expresses in antigen-presenting cell, which is an important target for regulating immune reaction because of regulating antigen-presenting. Cathepsin L participates in many special physiological processes, such as activation of prohomone, antigen-presentation, development of tissues and organs, etc. Cathepsin B distributes in liver, spleen, kidney, bone, nerve cells, interstitial fibroblasts, macrophages, etc, and stores in the form of zymogen in lysosome, which participates in many special physiological processes, such as activation of prohomone, antigen-presentation, development of tissues and organs, etc.
Cathepsin K (cat K) has been variously denoted as cathepsin O and cathepsin O2. Cathepsin K selectively expresses in osteoclast in great quantities, its substrate in physiological action is type I collagen of up to 95% content in organic matrix of bone. In addition, cathepsin K can degrade the osteopontin and osteoneckin of bone matrix, which is a cysteine protease that has highest expression and strongest osteolytic activity in osteoclast. The ability of degration to osteogenesis collagen for cathepsin K is more higher than any other enzymes, and athepsin K is a key enzyme in the process of bone resorption, which is also a hot point in the osteoporosis research in recent years. In the present, the FDA has not approved any anti-cathepsin K inhibitor, but some related organization protease inhibitors are in clinical studies.
Merck's odanacatib is in faster research progress, but because of some troubling signs of side effects in clinical studies, it is still in the clinical stage. The effect of cathepsin K is very important and very complicated on physiological processes in body. In order to avoid a broad-spectrum inhibition causing other than clinical side effects, the design and synthesis of efficient selective inhibitors is extremely urgent.